Stimuli-responsive polymer wormlike micelles

Accepted Manuscript Title: Stimuli-Responsive Polymer Wormlike Micelles Authors: Qirui Tian, Chenhong Fei, Hongyao Yin, Yujun Feng PII: DOI: Reference:

S0079-6700(17)30222-8 https://doi.org/10.1016/j.progpolymsci.2018.10.001 JPPS 1108

To appear in:

Progress in Polymer Science

Received date: Revised date: Accepted date:

22-10-2017 4-10-2018 8-10-2018

Please cite this article as: Tian Q, Fei C, Yin H, Feng Y, StimuliResponsive Polymer Wormlike Micelles, Progress in Polymer Science (2018), https://doi.org/10.1016/j.progpolymsci.2018.10.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Stimuli-Responsive Polymer Wormlike Micelles

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Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. China Polymer Research Institute, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, P. R. China

author: [email protected]

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Qirui Tiana, Chenhong Feia , Hongyao Yinb, Yujun Fenga,b*

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Graphical Abstract

Abstract

Smart soft materials comprising stimuli-responsive micelles represent an innovative imitation of materials found in nature. These morphologically multicolored assemblies

manifest versatile compliances in response to multiple triggers from environmental changes. Among these, asymmetric amphiphilic block copolymers afford elegant morphological structures in a number of giant micelles, including spheres, vesicles, and worms. Herein, we review the switching manifestation of polymer wormlike micelles (PWLMs) toward various stimuli, including heat, pH, CO2, redox, solvent, and multiple triggers reported so far. Besides, subsequent structural variation and macroscopic

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properties, such as viscosity, elasticity, and spontaneous “sol-gel” transition have been generalized and rationalized meticulously. Perspectives on promising prospects of

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smart PWLMs are presented in the conclusion.

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Keywords: Wormlike micelle; Block copolymer; Self-assembly; Stimuliresponsiveness

Table of Contents Nomenclature 1. Introduction 2. Thermo-responsive PWLMs

2.2 PWLMs exhibiting thermo-induced sol-gel transitions

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2.1 Thermo-thickening nonionic PWLMs

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2.3 Thermo-responsive PWLMs with conformation-specific self-assembly 3. pH-responsive PWLMs

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3.1 pH-responsive PWLMs of polyacid

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3.2 pH-responsive PWLMs of polybase

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3.3 pH-responsive PWLMs of polyampholyte

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4. CO2-responsive PWLMs

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3.4 pH-responsive degradable PWLMs

5. Redox-responsive PWLMs

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6. Solvent-responsive PWLMs

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7. Dual stimuli-responsive PWLMs 7.1 Dual stimuli-responsive PWLMs with designed end-groups 7.2 PWLMs with specific dual-responsive blocks

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8. Rheological features and applications of PWLMs 9. Conclusions and perspectives References

Nomenclature 2VP

2-Vinylpyridine

CMC

Critical micelle concentration

4VP

4-Vinylpyridine

CP

Cloud point

δ

Solubility parameter

CPBA

Carboxyphenylboronic acid

0

Zero shear viscosity

CPDB

2-Cyano-2-propyl dithiobenzoate

ζ

τb/τrep, parameter characterizing chain

microscopy

relaxation D2

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cryo-TEM Cryogenic transmission electron

A second generation of a poly(amido

τb

Breaking time

τrep

Reptation time

τR

Relaxation time

Φ

Volume fraction of the polymer

Фc

Percolation threshold

DEAEMA N,N-Diethylaminoethyl methacrylate

a0

Optimal area of the head group in

DEGMA

Doxorubicin

DBA

N,N-Dibutylacrylamide

DEA

N,N-Diethylacrylamide

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Dox

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Mole fraction of EO blocks

IEP

Isoelectric point

l

Kuhn length of the chain

lc

Length of the hydrophobic tail in

DLS

Dynamic light scattering

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fEO

N,N-dimethylacetamide

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DMAc

DMAEMA N,N-dimethylaminoethyl methacrylate N,N-dimethylformamide

DP

Degree of polymerization

DSC

Differential scanning calorimetry

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Poly(N,N-diethylaminoethyl methacrylate)

Packing parameter for assembling

EG

Ethylene glycol

amphiphiles

F

Poly(2,2,3,4,4,4-hexafluorobutyl

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DMF

amphiphiles

macro-CTA Macro-chain transfer agent

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v

Di(ethylene glycol) methyl ether methacrylate

amphiphiles

p

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amine)

methacrylate)

Volume of the hydrophobic chain in G

Storage modulus

AuNPs

Gold nanoparticles

G

Loss modulus

AA

Acrylic acid

GaAs

Gallium arsenide

GMA

Glycerol monomethacrylate

HEA

Hydroxyethyl acrylate

HEMA

2-Hydroxyethyl acrylamide

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N-Acryloyl-2,2-dimethyl-1,3-oxazolidine

Bd

Butadiene

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ADMO BzMA

Benzyl methacrylate

C*

Overlapping concentration for wormlike

HPMA

2-Hydroxypropyl methacrylate

micelles



Mean contour length

CAT

Critical aggregation temperature

Lexcl

Contour length of the chain with excluded

CGT

Critical gelation temperature

volume effects

Lw

Weight-average worm contour length

LCST

Lower critical solution temperature

LMA

Lauryl methacrylate

MAA

Methacrylic acid

Mn

Number average molecular weight

PETTC

4-Cyano-4-(2-phenylethane sulfanylthiocarbonyl) sulfanylpentanoic acid Polymerization-induced self-assembly

PKH 26

Dye encapsulated in PWLMs

PLGA

Poly(L-glutamic acid)

PLL

Poly(L-lysine)

PMMA

Poly(methyl methacrylate)

PPMA

3-Phenylpropyl methacrylate

trithiocarbonate-based RAFT chain

PPO

Poly(propylene oxide)

transfer agent

PPS

Poly(propylene sulfide)

NIPAM

N-isopropyl acrylamide

PTFMS

Poly(para-trifluoromethylstyrene)

NMR

Nuclear magnetic resonance

PWLMs

Polymer wormlike micelles

O

Poly(ethylene oxide)

Rw

Mean worm cross-sectional radius

OsO4

Osmium tetroxide

RAFT

OCL

Poly(ethylene oxide)-b-polycaprolactone

OEGMA

Oligo(ethylene glycol) methyl ether

MPs

Microparticles

MPETTC Morpholine-functionalized

P85

EO25PO40EO25

P123

EO20PO68EO20

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EO19PO43EO19

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P84

Poly-L-EG2Glu Poly(γ-(2-methoxyethoxy) esteryl-L-glutamate)

Reversible addition-fragmentation chain transfer polymerization

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methacrylate

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Multicompartment micelle

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MCM

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(g/mol)

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PISA

Reactive oxygen species

S

Styrene

S(q)

Structure function

SANS

Small-angle neutron scattering

SAXS

Small-angle X-ray scattering

SBM

Polystyrene-b-polybutadiene-bpoly(methyl methacrylate)

SLS

Static light scattering

tetraphenylporphyrin

SMA

Stearyl methacrylate

Poly(allylamine hydrochloride)

SWLM

Smart wormlike micelle

Polybutadiene

SPWLM

Smart polymer wormlike micelle

PCL

Polycaprolactone

TA

Tetraaniline

PEO

Poly(ethylene oxide)

TAX

Paclitaxel/Taxol

UCST

Upper critical solution temperature

WLM

Wormlike micelle

2-Formyl-5, 10, 15, 20-

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PB

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PAH

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Por

1. Introduction

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The supramolecular self-assembly of amphiphilic copolymers dispersed in a medium forming abundant micellar structures has attracted increasing interest in the past decade because of the colorful morphological appearances and underlying functional applications of these materials [111]. Among the multitudes of micellar species, including spherical, disk-shaped, wormlike, or vesicular, polymer wormlike micelles (PWLMs) are extremely appealing and highly versatile owing to their unique serpentine conformations and stronger mechanical properties compared with surfactant self-assemblies [1214]. In contrast to spherical micelles with fixed shapes in a linear “necklace-like” arrangement, PWLMs are uniform, elongated, and cylindrical aggregates with considerable flexibility [15,16], even though the uniaxial growth of spherical micelles is a vital step in the growth of these worms [17]. The entropically unfavorable one-dimensional packing of spheres is driven by the free energy difference between the amphiphilic polymer chains in the cylindrical body of the micelle and molecules located at the spherical end-caps, analogous to a similar phenomenon in surfactant micelles [18,19]. In the latter case, a versatile empirical rule for anticipating the anomalous aggregation is theoretically established based on the inherent molecular curvature of the associating elements [6,20], as characterized by a dimensionless “packing parameter” p: p=v/a0lc (1) where v represents the volume of the hydrophobic chain, a0 denotes the optimal area of the head group, and lc refers to the length of the hydrophobic tail (Figure 1). Israelachvili [21,22] summarized such a classical model for predicting the corresponding morphologies as follows: spherical micelles are favored when p  1/3, i.e., a block copolymer structure with a relatively high curvature, whereas cylindrical or wormlike micelles (WLMs) are formed when 1/3 p ≤1/2, and vesicles are formed when 1/2 ≤p ≤1. Armes et al. [6] extended the theory of the critical packing parameter of surfactants to block copolymers with covalently linked solvophilic and solvophobic blocks such that polymer micelles are formed to minimize the energetically unfavorable solvent-solvophobic interactions (Figure 1).

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Figure 1.

Morphology prediction of various self-assembled structures formed by amphiphilic block

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copolymers in a block-selective solvent based on packing parameter. The variation in the

formed structures is due to the inherent curvature of the molecule, which can be estimated by calculating the packing parameter, p. [6], Copyright 2009. Reproduced with permission from the John Wiley & Sons Inc.

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Although PWLMs are derived from specific amphiphilic aggregation, these micelles are distinctive morphological assemblies that can be formed within a narrow phase window, i.e., only if the relative volumes of the solvophilic and solvophobic blocks are balanced to moderate the molecular curvature. To bring forth a consecutive morphological sequence, p varies in response to environmental stimuli, such as surfactant concentration, temperature, pH, and salinity [2326], enabling an instantaneous response via both microscopic transformation and the corresponding macroscopic rheological response, which thus renders smart micelle systems sensitive to external triggers. Above all, the ceaseless untangling and reconstruction of the network activates stimuli-responsive gelation/degelation above the overlapping concentration (C*) of the worms, laying the foundation for the unobservable responsiveness of morphological hierarchies. In the case of aggregation of long chains, a comparatively elongated worm is more energetically favored compared to rod-like cylinders owing to the less-distributed incorporated end-defects. Meanwhile, under the influence of entropic demands and molecular frustration, end-caps and branch points of WLMs are marginally formed [6]. Macromolecules with varying chemical features positively self-assemble into giant worms, for instance, diblock polymers [27] and star-like terpolymers [28], together with various polyelectrolytes such as macromolecular surfactants [4], phytosterols [29], and polypeptides [30]. In contrast to these miniature counterparts, copolymer worms are generally more robust and offer the possibility of more applications [31], with potential in medical fields, such as in vitro and in vivo drug delivery [32] and in animal models [33]. In addition, PWLMs have also shown promise as impact modifiers that can increase the fracture resistance of commercially

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important epoxy resins [34] and as units of ceramic nanolines, achieved by positioning micelles comprising a core Fe atom on GaAs wafers [35]. Although PWLMs were putatively supported by the analogous principle of amphiphilic aggregation, these conformations were not observed or verified until the 1970s [36,37], decades after the discovery of giant spheres and vesicles [38,39], because of the narrow phase window. PWLMs started to emerge in a range of exploratory studies by Price [36,40], Kurata [41], and Emeis [42] teams, who reported an anomalous one-dimensional elongation of poly(styrene-isoprene) in certain organic solvents. Later, Eisenberg and co-workers established the incipient theoretical model to describe the various packing arrays of asymmetric copolymers, preliminarily outlining a series of diverse complex morphologies, including but not limited to spheres, worms, and vesicles [43], and developing a systematic understanding of morphogenic parameters [44]. Moreover, Eisenberg et al. [12] demonstrated the responsive rearrangement of PWLMs by introducing an ion-triggered morphological change, artistically broadening the horizons of PWLMs to smart soft materials and rendering the block copolymer assemblies more attractive. Subsequent developments from the Armes group [8,9,11] highlighted the intelligence and spontaneity of worm formation and reconstruction by demonstrating polymerization-induced self-assembly (PISA), a versatile in situ method that extends a soluble macromolecular stabilizer in a block-selective solvent. Following the first temperature-induced order-order transition engineered via PISA, Armes et al. [45] developed a relatively complete theory that has facilitated the incorporation of new features in the design of smart PWLMs. Since then, PISA has enabled pH-induced [46] and dual-stimuli-induced [47] morphological transitions of PWLMs and has shown potential as an overarching method for copolymer micellization. A practical advancement endowed by PISA was directly related to the feasibility of constructing morphological display by typical emulsion or dispersion polymerization in a hybrid homogenous/heterogeneous condition [11]. Morphological variation by traditional self-assembly routes has many restrictions, in that post-treatments are often involved by introducing a co-solvent or a pH-tuning agent under a relatively dilute concentration (1% < w/w) [20,48]. In comparison, PISA introduces a soluble polymer precursor for chain-extension in the selective solvent for the growing block, where an in situ microphase separation and micelle assembly gradually take shape along the extension of amphiphilic macromolecule. Meanwhile, the coinstantaneous chain growth drives the morphological variation from spheres to worms or vesicles, according to the relative volume ratio and solvent miscibility between the segments. Following the maturation of synthesizing PWLMs, smart materials have inspired interest in WLMs from a new perspective. As a special portion, smart wormlike micelles (SWLMs) have a distinct conformational characteristic, as their entanglement-favored architecture would allow instantaneous, radical, and dynamic

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changes in the micellar properties. More precisely, a morphological transition at the micelle level and a rheological variation at the solution level occur simultaneously in response to an external stimulus. Herein, we emphasize the transition to be “switchable” over “stimuli-responsive,” because it highlights the reversibility of the micellar smartness, i.e., p, along with morphological evolution once the external stimuli are removed. Inherently, self-assembled block copolymers, typically diblocks or triblocks, can be reversibly tuned between different micellar morphologies, and consequently, can exhibit distinct macroscopic rheological responses to certain stimuli [49]. Moreover, broad and flexible copolymer macrosurfactants can offer considerable advantages in the design of smart polymer wormlike micelles (SPWLMs) over their small molecular counterparts [50], particularly because of their optimal stability [31]. However, very few detailed reports to date have focused on elucidating the aspect of these “large-scale” associations. In these circumstances, although SPWLMs are confined to a relatively narrow phase window and the types of these materials are limited, we still chose to review the rapidly increasing interest in SPWLMs and the substantial progress made in this emerging area. In this review, we focus on the switchable responsiveness of SPWLMs, i.e., the instantaneous, radical, and reversible changes in PWLMs in response to environmental cues, such as heat, pH, CO2, redox, solvent, or combined stimuli, with each point of emphasis related to the latest development in that field. The explanations provided lead to an active and tailored instruction regarding micellar structure and the concomitant rheological response. Moreover, we forecast the currently unrecognized potential of PWLMs and their wide applications. 2. Thermo-responsive PWLMs

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Heat is one of the most commonly used stimuli, as it can be accurately controlled and conveniently applied in various situations. Generally, compared to common thermothinning (viscosity decrease with increasing temperature) micelles based on the Arrhenius law [51], thermo-thickening (viscosity increase with increasing temperature) micelles show more unique behaviors, and have gained particular interest [16]. To firmly distinguish between the two thermo-responsive behaviors, thermo-thickening micelles usually exhibit a peak in the viscosity-temperature curve at a critical temperature rather than a monotonic increase over the entire temperature range. In addition, it is appealing that several PWLMs undergo temperature-induced gel-sol macrophase transition, a representational characteristic for self-assembling worm systems. This section summarizes thermo-responsive PWLMs and separate them into three segments: thermo-thickening phenomena, thermo-induced gel-sol transitions, and thermal responsiveness under specific hydrophobic aggregation conditions.

2.1 Thermo-thickening nonionic PWLMs

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Compared to the extensively reported thermo-thickening behavior of WLMs formed from small molecule surfactants, the thermo-thickening behavior of PWLMs has been scarcely studied because of the complexity in the preservation of their stability in the narrow phase window. Herein, we focus on nonionic PWLMs constructed by polyalkoxylate blocks—apparently a unique case based on thermo-thickening polymer worms. Poly(ethylene oxide) (PEO) a typical nonionic, thermo-sensitive material, is generally considered to be a biocompatible polymer for pharmaceutical, cosmetic, and medical applications [52]. The water solubility of PEO chains is influenced by temperature, as the hydration of the oxyethylene species can be directly tuned by thermal alteration [29]. With increasing temperature, the hydrosoluble nonionic PEO chains gradually dehydrate, leading to an upper miscibility gap in aqueous solution, commonly referred to as the cloud point (CP) [53]. Similarly, poly(propylene oxide) (PPO) exhibits a lower critical solution temperature (LCST) between 10 °C and 20 °C in dilute aqueous solutions [1]. Hence, from a structural perspective, an aggregation reconstruction of block copolymer PEO-PPO in solution would occur once the temperature is raised, inducing smart thermo-responsiveness. Because of the miscibility gap under thermal alteration, diblock PEO-PPO and triblock PEO-PPO-PEO copolymers (Figure 2), also known as Pluronics, are the most frequently studied thermo-sensitive polymers, able to self-assemble into micelles with multiple morphologies. Pluronics are widely used in diverse applications, such as detergency, emulsification, and lubrication, among others [54]. Alexandridis and Hatton [1] meticulously reviewed the association properties of the PPO-PEO-PPO triblock copolymers in aqueous solutions, providing a comprehensive scenario about how factors such as concentration, additives, and solution temperature, affect the micellar properties. Such triblock copolymers generally exhibit thermodynamic micellization behavior; in particular, the aggregating structure displays temperaturedependent response. Mortensen and Pedersen [55] summarized in detail the structural features of the Poloxamer EO25PO40EO25 (P85), as determined by small-angle neutron scattering (SANS). Particularly, they noticed that the polymer micelle, which is spherical with a hard PPO core and a flexible PEO corona at ambient temperature, experiences unidimensional elongation at 70 °C. The origin of this change might be related to the expansion of hard spheres at elevated temperatures [56], which eventually led to maximum stretching of the linear PPO chain just below 70 °C. Therefore, further heating converts the non-expandable spheres to elongated ellipsoids, which decreases intermicellar interactions and avoids the entropically unfavorable conformation [57], causing uniaxial micellization. Pluronic copolymers with suitable PEO weight fractions have been reported to grow

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into entangled micelles. Notably, only P85 with Mn=4,600 gmol1 (PEO weight fraction ~0.5) and EO19PO43EO19 (P84) with Mn=4,200 gmol1 (PEO weight fraction ~0.4) could grow into entangled worms in aqueous solutions [54,55]. Subsequent studies qualitatively predicted the sphere-to-rod transition of Pluronic copolymers based on mean-field lattice theory [58], and pulsed field gradient nuclear magnetic resonance (NMR) [59]. However, these reports provided no direct evidence for the micellization and elongation of PWLMs. Waton et al. [60] observed a dramatic increase in the viscosity of P84 in 2 M NaCl solution upon heating when the polymer concentration was higher than 0.5 wt% (Figure 2A). They found that the zero-shear viscosity (0) increased by a factor of 105 between 30 and 40 °C (below the CP of 43 °C), which cannot be explained by a simple sphere-to-rod transition, during which the viscosity increases by only tenfold [61]. More recently, the Schosseler team [62] studied this abnormal finding using SANS, dynamic light scattering (DLS), and viscometry. They determined that the significant increase in 0 between 30 and 40 °C could be explained by the transition from spherical micelles to entangled WLMs. According to the combined SANS and static light scattering (SLS) data shown in Figure 2B, the shape factor at 40 °C is typical for WLMs because of a high Lexcl/l value (≈20, Lexcl refers to the contour length of the chain with excluded volume effects, and l denotes the Kuhn length). The PWLMs exhibited a coil-like conformation [63], in agreement with the recent results of Khimani et al. [64] observed a distinct elongation from the DLS results shown in Figure 2C. The entanglements are responsible for the huge increase in solution viscosity upon heating above the CP [61,62]. By means of differential scanning calorimetry (DSC), Lof et al. [65,66] confirmed that the Pluronic homologue EO20PO68EO20 (P123) underwent transition from sphere to rod at approximately 60 °C, demonstrated by the calculated enthalpy change at about 10 kJmol-1. Moreover, it was proved that a mixed micelle with a surfactant would surprisingly decrease the critical micelle temperature of the pluronic, indicating a versatile and convenient method for designing SPWLMs. Consistent research successively observed the lengthened micellization responses of EO17PO60EO17 [67] and EO27PO61EO27 [68] at elevated temperatures. Although no electron microscopy images were provided to directly confirm the formation of WLMs, PEO-PPO copolymers (with proper hydrophilic/hydrophobic ratios and added salts) can be added to the toolbox for preparing thermo-responsive WLMs because of their ability to undergo a temperature-induced sphere-to-worm transition.

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Figure 2.

Structures of thermo-thickening nonionic amphiphiles bearing PEO and PPO blocks. (A) Evolution of zero-shear viscosity (η0) of 4 wt% P84 in 2 M NaCl solution with

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temperature. (B) Variation in structure function S(q) with temperature for Φ (Volume fraction)=5×103. Each curve combines SANS and light scattering data. (C) Hydrodynamic diameters of 5% P84 at various temperatures. [60, 64], Copyright 2004,

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2014, respectively, [62], Copyright2005. Reproduced with permission from Taylor & Francis and the American Chemical Society, respectively.

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In general, nonionic PWLMs based on hydrophilic PEO blocks can undergo a striking thermoviscosity process produced by multi-state morphological transitions and subsequent entanglement of the flexible aggregates. When the temperature is increased, micellar growth becomes favorable as soon as water becomes a poor solvent for the dehydrated PEO and PPO blocks [16,69,70]. 2.2 PWLMs exhibiting thermo-induced sol-gel transitions In this review we use the term “gel” to refer to material with a dynamic rheological

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behavior characterized by G > G, with G' essentially independent of frequency over a very wide range in frequency [16],. In dilute solutions, surfactant-based WLMs are initially characterized as a viscoelastic Maxwellian fluid with a certain relaxation time [71], while under certain conditions or with certain additives, WLMs are considerably strengthened, imparting a gel-like behavior to the solution. [16,72,73]. In other words, the “gel” constructed by surfactant molecules displays an effective “sol-gel” transition, which, in appearance, reflects the intrinsic structural transformation within the phase change. From the perspective of experimental investigation, this visually observable feature has been highly valued because of its bridging between constructional response and smart soft materials. This section reviews surfactantanalogue PWLMs with distinct rheological behaviors that undergo “sol-gel” transitions in response to thermal stimuli.

Figure 3.

(A) Amphiphiles exhibiting a thermo-induced gel-sol transition: (a) PGMA-PHPMA, (b) PGMA-P(HPMA-stat-DEGMA), (c) PS-P(HPMA-stat-DEGMA), (d) PEO-PDEAm-

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PDBAm, (e) PLMA-PBzMA, and (f) PSMA-PBzMA. (B) Representative TEM images of the reconstruction of diblock copolymer P(DEGMA29-stat-HPMA6)-b-PS in water upon cooling from 70 °C to room temperature as a latex and when different amounts of toluene, i.e., (A) 0 µLmL1, (B) 20 µLmL1, (C) 40 µLmL1, (D) 80 µLmL1, and (E) 160 µLmL1, were added to plasticize the core. (C) Temperature dependence of the apparent degree of solvation of the PBzMA block, as determined by variable temperature 1H NMR spectroscopy of PSMA13-PBzMA96 nanoparticles in d26-dodecane (the inset shows

assigned partial spectra from which the degrees of solvation were determined). [82], Copyright 2016, [86], Copyright 2017. Reproduced with permission from the Royal Society of Chemistry and John Wiley & Sons Inc, respectively.

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Blanazs et al. [45] developed a novel biocompatible hydrogel with the excellent sterilizability that is crucial for biological applications [74]. The free-standing hydrogel comprises PWLMs formed via the PISA of PGMA-PHPMA (Figure 3a) in an aqueous solution. 2-Cyano-2-propyl dithiobenzoate (CPDB) was selected as the RAFT chain transfer agent to synthesize the PGMA (macro-CTA), which in turn was employed to further sustain the polymerization of HPMA and thus construct the copolymer as a macro-chain transfer agent. At 21 °C, the gels were formed due to the entanglement of the PWLMs, whereas gel dissolution occurred on decrease of the temperature 4 °C, and regelation occurred reversibly upon subsequent heating (Figure 4A). To directly confirm the reversible nature of the worm-to-sphere transition after two consecutive temperature cycles between 5 and 25 °C, small-angle X-ray scattering (SAXS) was performed on a 10% w/w aqueous dispersion of PGMA54PHPMA140 diblock copolymer. In the Guinier region (low q), where WLMs are relatively intense, a clear distinction between spheres (zero gradient) and worms (gradient close to −1) was observed in the I(q) vs (q) plot (Figure 4B). Besides, almost overlaid SAXS plots revealed a perfectly superimposable pattern at the two thermal cycles between 5 and 25 °C, indicating the excellent morphological reversibility in the semi-concentrated aqueous solution. This thermo-reversible behavior enables the efficient removal of micro-sized bacteria in a low-viscosity spherical state at 4 °C, offering an opportunity for facile sterilization of the worm gels (Figure 4C).

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Figure 4.

(A) Reversible transition of PGMA54-PHPMA140 between 21 °C and 4 °C. (B) SAXS pattern recorded for a 10 w/w % PGMA54-PHPMA140 aqueous copolymer dispersion at

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both 25 and 5 °C for two thermal cycles. (C) Sterilization of copolymer worm gels by cold ultrafiltration. [45], Copyright 2012. Reproduced with permission from the American

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Chemical Society.

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The thermo-responsive degelation proved to be induced by a worm-to-sphere transition [6]. With decreasing temperature, the degree of hydration of the coreforming PHPMA chains increases, improving their mobility and reducing the interfacial tension between the two blocks. This hydration process immediately increases the copolymer curvature and thus reorganizes the PWLMs into spheres. Since the worm-to-sphere transition is fully reversible, it offers a novel and highly convenient route to sterilizable biocompatible gels. In subsequent research, the same group [75,76] attempted to regulate the gel strength and critical gelation temperature (CGT) by manipulating the length of the core-forming PHPMA chains, as longer PHPMA blocks require a greater degree of hydration to induce the worm-to-sphere transition, realized only when the temperature is decreased gradually. Cunningham and coworkers [76] used the self-assembly of a core-forming block comprising a statistical mixture of HPMA and the comparatively more hydrophilic

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di(ethylene glycol) methyl ether methacrylate (DEGMA) to improve a well-known smart worm gel. PDEGMA is a thermo-responsive methacrylate polymer with an LCST of approximately 28 °C; this temperature can be tuned to 32 °C (i.e., the LCST of PNIPAM) simply by copolymerizing the 5 mole percent of oligo(ethylene glycol) methacrylate [7779]. Therefore, PDEGMA is regarded as a desirable analogue and substitute for PNIPAM with better biocompatibility, low toxicity, and antifouling properties [80]. In particular, PGMA59-P(HPMA91-stat-DEGMA39) (Figure 3A) had a CGT of 31 °C, sufficiently close to the physiological temperature (37 °C). Similar to the results of Jia and Monteiro [81], the addition of a salt decreased CGT of the PNIPAM-b-PS copolymer WLMs, as salts lower the LCST of PNIPAM. This deliberate regulation effectively broadened the temperature-responsiveness of the entangled worm gels and rendered it biocompatible. Soon after, the Davis group [82] reported a thermally responsive P(DEGMA29-stat-HPMA6)-b-PS terpolymer (Figure 3A) that underwent a predictable multistate morphological transition upon reducing the temperature, as shown in Figure 3B. Toluene was chosen as the plasticizer for tuning the morphology because of its similar solubility parameter (δ) to that of the PS cores (δPS=16.6–20.2, and δtoluene=18.2) [83]. Sun et al. [84] broadened the scope of smart worm gels by establishing rapidly responsive PWLMs of PEO45-PDEAm41PDBAm12 (Figure 3A), induced by heating. The rapid transition of the triblock copolymer was ascribed to the ability of interchain hydrogen bonds formed after dehydration to kinetically trap the micelles and retard further rearrangement. Because PISA represents a potentially definitive option for the formation of smart diblock copolymer nano-objects, it was further investigated to make novel and attractive discoveries. Fielding et al. [85] reported a new RAFT non-aqueous dispersion polymerization that enables the preparation of a range of poly(lauryl methacrylate)-poly(benzyl methacrylate) (PLMA-PBzMA) diblock copolymer (Figure 3A) nano-objects in the non-polar solvent n-dodecane with 20 wt% solids. As anticipated, the entangled PLMA16-PBzMA37 worms formed free-standing gels at 20 °C and then underwent degelation upon heating above the CGT of 47 °C via a worm-to-sphere order-order transition. The smart thermo-responsiveness of the polymer was demonstrated to be reversible when a regelation occurred upon decreasing the temperature from 90 °C to 20 °C. The above temperature-induced morphological transition was ascribed to the subtle change in the relative volume fractions occupied by the PLMA stabilizer segment and the core-forming PBzMA segment. As the temperature increases, the ingress of solvent into the worms leads to preferential solvation of the core-forming PBzMA segments nearest to the PLMA stabilizer chains. More specifically, the solvated PBzMA segments became fairly flexible after surface plasticization, which lengthened the effective stabilizer blocks and shortened the core-forming blocks concomitantly. Consequently, the molecular curvature of the diblock chains increased, which most

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likely caused the worm-to-sphere transition via a sequential budding mechanism. Although the aforementioned transformation is essentially reversible, it is noteworthy that this thermally induced change is largely irreversible on an experimental time scale of hours when conducted in a highly dilute solution (~0.1% w/w), due to the relatively low fusion probability for multiple disperse spheres. In a most recent study, this surface plasticization effect was succinctly verified by variable temperature 1H NMR spectroscopy of a 5.0 wt% PSMA13-PBzMA96 (Figure 3A) copolymer dispersed in d26-dodecane [86]. Despite being comparatively poorly solvated initially, the core-forming PBzMA block gradually diffused into the solvent upon heating from 20 °C to 150 °C, inducing an order-order morphological transition from vesicles to PWLMs and distinct gelation. Since the degree of solvation for the PSMA block remained steady during solvent ingression, the conspicuous alteration in the relative area ratio intuitively substantiates the occurrence of surface plasticization (Figure 3c). Hydrogels have potential uses in diverse fields of research, such as tissue engineering, nanotechnology, and biopharmaceuticals. Certain PWLMs have been verified as gelators with temperature reaction, a feature that grants them unique superiority for applications in smart gels. Long and flexible worm gels with reversible thermoresponsiveness have shown considerable advantages over conventional gelators such as polymers [8789] and peptides [90,91].

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2.3 Thermo-responsive PWLMs with conformation-specific self-assembly

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As mentioned above, traditional copolymers generally have non-specific hydrophobic interactions with each other, whereas numerous biopolymers of natural origin interact via more complex and specific ways in the presence of an external stimulus and are thus particularly promising as smart materials. For instance, copolymers with a polypeptide block have been investigated for conformation-modulated self-assembly. Polypeptide materials are distinctively attractive because of their unique secondary structures [92,93]. Two different temperature-controlled levels of polypeptide-based self-assembly with heat-induced gelation responsiveness were used to develop thermo-responsive PWLMs by Shen and coworkers [30]. A diblock hydrophilic copolymer, poly(ethylene glycol)45-b-poly(γ-(2-methoxyethoxy)esteryl-L-glutamate)43 (PEG45-b-poly-L-EG2Glu43), was synthesized, in which the poly-L-EG2Glu homopolypeptide block notably underwent a thermo-triggered phase separation after multiple heating-cooling-heating cycles because of a secondary structure transition from an α-helix to a β-sheet [94,95]. As the temperature of the aqueous copolymer solution initially increased above the CP of poly-L-EG2Glu (53 °C) and then reduced to its initial value, the polypeptide block distinctly underwent dehydration/rehydration; meanwhile, reversible self-assembly of the PWLMs was observed. Even more appealing was that a long thermal-annealing time was found to drive a conformational transformation from PWLMs to one-dimensional nanoribbons.

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A plausible mechanism for the two-level thermo-triggered self-assembly of PEG45-bpoly-L-EG2Glu43 based on the designed diblock structure and the cooperation between the two blocks was proposed. Regarding the thermal aspect, when the temperature initially increased above the CP of poly-L-EG2Glu, the polypeptide block became hydrophobic after the LCST transition, and the hydrophilic copolymer immediately turned into an amphiphile, resulting in the packing of the PWLMs because the poly-LEG2Glu43 block has a greater volume fraction than the PEG block. In addition, on the experimental time scale, the polypeptide block underwent a secondary conformation transition from α-helix to β-sheet during a long-term thermal annealing above the CP. This transition was caused by the hydrogen bonding rearrangement between polypeptide chains from intramolecular to intermolecular (Figure 5A). Since the conformation-specific intermolecular hydrogen bonding favored the parallel or antiparallel arrangement of the copolymers, multilayer nanoribbons were obtained. The TEM images shown in Figure 5A verified this proposed mechanism. This study combines the non-specific reversible hydrophobic interaction characteristic with the conformation-specific biomolecules, thus offering an additional parameter to tune the nature of molecular assemblies. Subsequent research has complemented the topological diversity of thermosensitive poly-L-EG2Glu by verifying the conformational-specific sphere-to-worm transition with increasing molecular weight [96].

Figure 5.

(A, left) α-Helix conformation of PEG45-b-poly-L-EG2Glu43 and schematic illustration of its thermo-induced self-assembly; (A, right) TEM image of PWLMs and nanoribbons undergoing annealing-induced conformation transition. (B) Hypothetical mechanism of

conformation-specific formation of wormlike aggregates by TA-PHEA5-PNIPAM10. [30], Copyright 2013. Adapted with permission from the American Chemical Society; [97], Copyright 2015. Reproduced with permission from John Wiley & Sons Inc.

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Topological sequence plays an essential role in copolymer micellization. Wu et al. [97] used a pair of sequentially permuted amphiphilic triblock polymers as controlled tails and observed a divergent morphological response because of the different amphiphilic locations. They synthesized tetraaniline-b-poly(N-isopropyl acrylamide)b-poly(hydroxyethyl acrylate) (TA-b-PNIPAM-b-PHEA) and TA-b-PHEA-bPNIPAM with an unambiguous structure; the only difference between these two polymers was the order in which the blocks were connected. In terms of solvent affinity, TA can be classified as hydrophobic under neutral or alkaline conditions, while block PHEA is hydrophilic and block PNIPAM undergoes a hydrophilic-tohydrophobic transition at temperatures above its LCST. When cooled from 45 °C to 20 °C in a DMF/water mixture, the self-assembled TA-b-PHEA-b-PNIPAM spheres extended into PWLMs, whereas TA-b-PNIPAM-b-PHEA showed no comparable responsiveness under identical conditions. When the temperature of the assembled aggregate dispersion was reduced below the LCST of PNIPAM, the PNIPAM segments started to migrate from the middle layer (core) of the bilayer structure to the outer layer (shell) because of its hydrophilic inversion (Figure 5B). This morphological responsiveness requires a specific block arrangement, as the attachment of TA would undoubtedly impede PNIPAM from migrating into the solvated shells. Thus, we can conclude that thermo-responsive PWLMs have some common characteristics. All the introduced thermosensitive micelle types undergo or are inferred to undergo a worm-to-sphere transition upon heating, which is accompanied by an abrupt increase in viscosity or a sol-gel transition. The entangled structure is responsible for the significantly different behaviors at higher and lower temperatures.

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3. pH-responsive polymer WLMs

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Conformation change of polymer micelles trigged by pH is a ubiquitous response and has been extensively studied. Generally, when a designed pH-responsive chemical group is attached, ionizable micelles exhibit behavior that is dependent upon the chemical environment [98]. The ionization-induced conformational transition from a collapsed state to a swelled state is essentially driven by the osmotic pressure exerted by the mobile counter ions neutralizing the network charges [99]. According to their molecular features, pH-sensitive polymers are categorized into polyacids, polybases, and amphoteric polymers characterized by specific ionizable pendants, which cause each polymer to have a specific pKa. As the pH is increased above the pKa of, for example, a polyacid, it becomes deprotonated and acquires a negative charge.

Conversely, when the pH is decreased below its pKa, a polybase becomes protonated and positively charged, whereas an amphoteric polymer exhibits a much more sophisticated assembling behavior [100]. The exceptional capabilities of PWLMs have contributed to pH-sensitive micelles, becoming predominant in the smart soft matter field [16,98,100103]. 3.1 pH-responsive WLMs of polyacid

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The carboxylic group is the common acidic pendant group of weak polyacids. Typically, polyacids bearing the carboxylic group have a pKa of approximately 56. Under alkaline conditions, electrostatic repulsion between the deprotonated groups on the polyacid imparts a momentum to re-form the self-assembled state [100].

Figure 6.

(A) pH-responsive polyacids reported to form PLWMs: PBd-b-PMAA and HOOCPGMA-PHPMA. (B) Zeta-average diameter and electrophoretic potential measured as a function of solution pH upon shifting from high to low pH (top) and from low to high pH (bottom). (C) TEM micrographs of negatively stained structures formed upon increasing the pH from 4 to 11. [104], Copyright 2009. Reproduced with permission from the Royal

Society of Chemistry.

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The Battaglia group [104] reported the pH-controlled assembly of polybutadienepoly(methacrylic acid) copolymer (PBd-b-PMAA) (Figure 6A) into putative switchable WLMs. Large vesicles were formed at a low pH in copolymer solutions. As the pH increased to 8, the vesicles transformed into WLMs, and at pH 10, spherical micelles were formed. The block copolymer was synthesized via the sequential anionic polymerization of butadiene and t-butyl methacrylate, and the poly(t-butyl methacrylate) segment was hydrolyzed by refluxing with HCl in dioxane. In addition, the block copolymer PBd24-PMAA10 was synthesized. The concentration of the block copolymer in a dioxane/methanol (9:1, v/v) solution was 0.4% (w/v). Figure 6B shows the pH dependence of the zeta-average diameter and zeta-potential transition of the block copolymer. When pH is lower than 6, vesicles dominate the morphology, whereas increasing the pH causes the structures to gradually change into worms. When pH increases to 10, the worm micelles transform into spherical micelles, and the resulting morphological arrangement is depicted in Figure 6C. Unfortunately, micelles formed at a high pH do not transform into WLMs and vesicles at a lower pH as quickly as those modified by increasing the pH because the electrostatic repulsion between the PMAA blocks slows the transition from spherical micelles at a higher pH to WLMs and vesicles at lower pH, despite the vesicles being thermodynamically stable. The pH-induced collapse of the vesicles into worms suggests the potential application of this block copolymer as nanoreactors that can be readily emptied to carriers and deliver drugs intracellularly in response to pH change upon endocytosis [104]. Thermo-triggered smart PWLMs were systematically reported by Armes and coworkers [45,75,76,85]; however, stimuli-responsive PISA, involving more creative molecular and structural designs, has been demonstrated to be generally more versatile. Lovett et al. [105] synthesized a nonionic diblock copolymer PGMAPHPMA that exhibited a reversible pH-responsive behavior. The diblock copolymer was terminated with a pH-sensitive carboxylic acid group with a pKa of approximately 4.7 using 4-cyano-4-(2-phenylethane sulfanylthiocarbonyl) sulfanylpentanoic acid (PETTC) as a chain transfer agent. In a 10 wt% solution under mildly acidic conditions, the resulting HOOC-PGMA56–PHPMA155 (Figure 6A) worms formed a soft, transparent gel. When the solution pH was increased above 4.7, the ionization of the terminal carboxylic acid drove the conversion of the worm gels into free-flowing spheres. The order-order transition occurred because the pHtriggered ionization increased the degree of hydration of PGMA, i.e., the stabilizer block, and ultimately decreased the packing parameter, p, of the copolymer chain. Notably, the PGMA-PHPMA amphiphilic copolymer worm gels could also respond to thermal stimuli, according to the results of Blanazs et al. [45].

3.2 pH-responsive WLMs of polybase

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Primary, secondary, and tertiary amine groups as well as imine functionality gain protons under acidic conditions and release them under a basic environment. Consequently, these moieties are frequently utilized in designing polybases. Poly(4vinylpyridine) (P4VP) and poly(2-vinylpyridine) (P2VP), representative polybases that form SPWLMs, undergo a phase transition below pH 5 owing to the deprotonation of the pyridine groups [106,107]. Yang et al. [108] developed a promising pH-responsive controlled delivery system based on polystyrene-b-poly(4vinylpyridine) (PS-b-P4VP), as shown in Figure 7A. This block copolymer selfassembles into spherical and WLMs with PS cores and P4VP coronas in aqueous solutions. In addition, the formed WLMs exhibit valuable pH sensitivity due to the protonation of pyridine at a low pH and deprotonation at a high pH, which cause alterations of the micelle morphology.

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Figure 7.

(A) pH-responsive polybases that form PLWMs: PS-b-P4VP, PEG-b-PADMO, and MPETTC-PGMA-PHPMA. (B) TEM images and corresponding digital photographs of MPETTC-PGMA50-PHPMA140 diblock copolymer nano-objects at different pH values. (C) Schematic illustration of reversible worm-to-sphere transition that occurs when morpholine-functionalized PGMAx-PHPMAy diblock copolymer worms undergo a pH switch upon addition of acid or base. Addition of salt to a spherical dispersion at pH 3 can also induce sphere-to-worm transition. [47], Copyright 2016. Reproduced with permission

from the Royal Society of Chemistry.

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In this controlled delivery experiment, doxorubicin (Dox) was used as the cargo because it is not only an anti-cancer drug, but also a fluorescent agent, which enables the close monitoring of its release. The solution of PS-b-P4VP block copolymer with different Dox concentrations in DMF was immersed in water, and then casting blades were used to shape the PS-b-P4VP membrane onto the glass plates. Entangled WLMs with different diameters were observed in the aqueous solutions of both PS43k-bP4VP59k and PS120k-b-P4VP25k. Further study of the release behavior of Dox encapsulated in PS43k-b-P4VP59k indicates that the delivery is pH dependent., The drug release accelerated at higher pH, while at a lower pH, no acceleration was observed. The pyridine block of the copolymer, which forms the corona shell of the micelle, is deprotonated at a high pH, causing the shrinkage of pyridine units that exposes the Dox-loaded PS core to the buffer solution and accelerates the diffusion of Dox. As revealed by the release data, it is notable that negligible amounts of Dox were released for the entire duration at pH 4.0 to 7.0, while about 10 wt% was released after 5 h as the pH value increased to 9.0. The pH-dependent rate was controlled by the protonation of the pendant pyridine. At a low pH, the pyridine groups are protonated, and the blocks extend to reduce charge repulsion. The pyridine units began to overlap and form a protective network to prevent the released Dox from diffusing out of the membrane [108]. Cui et al. [109] synthesized a novel amphiphilic diblock copolymer bearing acidlabile oxazolidine moieties, followed by the release of guest molecules. Notably, the assembly and disintegration of this copolymer, as well as the subsequent release of guest molecules, could be controlled by tuning the pH. Moreover, the results showed that copolymers with different block ratios lead to different aggregate morphologies. Among the three kinds of aggregate morphologies (spherical micelles, WLMs, and vesicles), the WLMs exhibit some temperature-sensitive properties [109]. To go a step further toward the morphological sequence, a series of copolymerized poly(ethylene glycol)-b-poly(N-acryloyl-2,2-dimethyl-1,3-oxazolidine) (PEG-b-PADMO) with different component ratios were obtained by the RAFT technique (Figure 7A), i.e., E45A18, E45A28, E45A47, and E45A88, where EmAn represents PEG-b-PADMO having m EO units and n ADMO units. When the pH of the copolymer solution is increased, the hydrophobic PADMO blocks are hydrolyzed into hydrophilic poly(2-hydroxyethyl acrylamide) (PHEAM) blocks, followed by micelle disruption and the release of loaded Nile Red. The disintegration of hydrolysis-induced PWLMs could raise interests to explore novel kinds of stimuli-responsive micelle materials and potential biotechnological applications by acid-labile modifications. Another unexpected phenomenon is that the WLMs assembled from E45A47 show a somewhat thermo-responsive behavior. At a concentration higher than 2 mg mL1, E45A47 solutions represented a heat-induced reassembly, during which the transparent

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solution at 4 °C gradually became cloudy at room temperature. In contrast, no such behavior was observed in either E45A28 or E45A88 solutions under the same condition. This observation suggests that with a suitable composition, this type of block copolymer may exhibit thermally induced phase transition [109]. The authors did not discuss this transition in detail, and further investigation could not relate this phase transition to the morphological variation of the micelles. Subsequent research by the Armes group [47] demonstrated that the morpholinefunctionalized PGMA50-HPMA140 copolymer MPETTC-PGMA50-HPMA140 (Figure 7A) formed free-standing gels at pH 7.07.5. MPETTC is a designed morpholinefunctionalized trithiocarbonate-based RAFT chain transfer agent. This polymer constitutes a complementary pH-responsive polybase to carboxylate-modified polyacids [105]. The protonation/deprotonation of the terminal morpholine group resulted in a reversible worm-to-sphere morphological transition, thus leading to in situ degelation at pH 3 and regelation upon returning to pH 7 at 15 wt% solids because of the hydration-induced reduction of the packing parameter, p. Acid titration studies indicated that the pKa of this MPETTC-PGMA50 precursor is approximately 6.3. Moreover, as the pH was continually decreased below 3 to 0.9, the re-formation of weaker worm gels was observed due to a screening effect of the excess HCl, which lowered the zeta potential of the PWLMs, resulting in a recombination from spheres to worms. In this case, the re-formed worms were weakly entangled owing to the electrostatic repulsion between the protonated morpholine end-groups. The various morphologies of the polymer and its intrinsic pH responsiveness are depicted in Figure 7B and 7C, respectively. Poly(N,N-dimethyl aminoethyl methacrylate) (PDMAEMA) and poly(N,Ndiethylaminoethyl methacrylate) (PDEAEMA) are also common pH-sensitive polybases with amine groups in their side chains. Because of their thermoresponsiveness around their LCSTs, they are typical dual stimuli-responsive species, and will be discussed later in Section 7.

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3.3 pH-responsive WLMs of polyampholyte

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Polyampholytes, containing both acidic and basic groups, exist mostly as zwitterions in a certain range of pH in dispersed or assembled forms in solutions, and respond to pH variation consecutively. When functionalized by certain segments, polyampholytes experience multiple protonation states in distinct pH regimes characterized by the isoelectric point (IEP) [110,111]. Particularly, at pH < IEP, positive charges predominate due to the protonation of the acidic segments; at pH > IEP, negative charges govern because of the deprotonation of the basic units; and at an intermediate pH around the IEP tuned by the acidic/basic ratio, the polymer chains aggregate via the electrostatic interaction between mutually neutralized moieties.

(A) Assembly of PS33-P2VP126-b-PAA69 unimolecular micelles and TEM images of PS-

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Figure 8.

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There has been increased interest [112115] in smart micellization based on polyampholytes in recent years, in which SPWLMs are innovatively positioned.

core-(P2VP-b-PAA) star conformation as well as the corresponding self-assemblies at (a) pH 1.4 (unimolecular micelles), (b) pH 1.6 (WLMs), (c) pH 2.0 (multicore micelle), (d) pH

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7.5 (unimolecular micelle), (e) pH 8.5 (associated unimolecular micelle approaching network-like assemblies), and (f) pH 11.8 (multicompartment multimolecular micelles). (B) Chemical structure of PLL-b-D2-(PLGA)4 linear dendritic copolyampholyte (left) and

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schematic illustration of its pH responsiveness in aqueous solutions (right). [116], [114] Copyright 2011, 2013, respectively. Reproduced with permission from the Royal Society of Chemistry and the American Chemical Society, respectively.

Multiarm star-shaped polyampholytes based on (polystyrene)n-core-(poly(2-vinylpyridine)-b-poly(acrylic acid))n (PSn-core-(P2VP-b-PAA)n) are known to be pH sensitive in dilute solutions, as depicted in Figure 8A [116]. The novel amphiphilic terpolymer bearing PS hydrophobic arms and P2VP-b-PAA diblock copolymer

amphoteric arms exhibited multilevel assemblies that were dependent on the pH of the medium, including PWLMs. The diblock P2VP-b-PAA arms comprising an amphoteric combination of a polyacid (PAA) and a polybase (P2VP) endowed the polymer with an IEP at pH 4–7; simultaneously, the PS cores facilitated hydrophobic attractions within the micelles. Inter-star H-bonding of the corona segments robustly promoted stable micellization and transition.

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Chen and co-workers [114] recently described a linear dendritic block copolyampholyte of amino acid derivatives, poly(L-lysine)-b-D2-(poly(L-glutamic acid))4 (PLL-b-D2-(PLGA)4) (Figure 8B), in which D2 is a second-generation poly(amido amine). Structurally, such a copolyampholyte achieved divergent pH responsiveness by connecting the linear amino PLL arm to the dendritic carboxylic PLGA periphery. The dual classes of amino acids with weakly acidic and basic groups enabled a coupled pH-induced coil-to-helix conformation transition accompanied by a decrease in ionization and dissolution [117]. Concurrently, a corecorona inversion involving PLL-cores and PLGA-cores occurred in the micelles. Consequently, self-assembled aggregates with various morphologies, including WLMs, have been obtained by increasing and decreasing the solution pH.

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3.4 pH-responsive degradable PWLMs

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Inspired by the pH-dependent hydrolysis behavior of polyesters, the Discher group [118] investigating the application of WLMs comprising poly(ethylene oxide)-bpolycaprolactone (PEO-b-PCL) (Figure 9A) for drug delivery. Particularly, they studied the drug delivery ability of these PEO-PCL worm micelles as compared with their spherical counterparts and closely monitored the degradation of the micelles by fluorescence microscopy [50]. The WLMs were found to have obvious advantages over their spherical counterparts in terms of drug loading efficiency and stability [14,118]. Moreover, each WLM was observed to load 1,000 times more drugs than an average spherical micelle [50]. The degradation of the PCL blocks in water induced the automatic transformation from the worm micelles into spherical ones, which enabled the release of the entrapped drug.

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Figure 9.

(A) pH-responsive block polymers PEO-b-PCL and PAH-g-Por form degradable PWLMs . (B) Degradable OCL worm micelles spontaneously shorten in length with time and thus

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generate spherical micelles. (a) Visualization of the shortening by fluorescence microscopy. (b) Contour length distribution during the shift toward spherical micelles,

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fitted by Gaussian or Lorentzian for ∼200 worms. (c) Mean contour length of the OCL worms decreases with time under physiological conditions. (C) Proposed mechanism for the formation of pH-sensitive decomposition-assembled structures of PAH-g-Por MPs at pH 14. [50], [119], Copyright 2006, 2015, respectively. Reproduced with permission

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from Elsevier Ltd and the Royal Society of Chemistry, respectively.

In a later work [50], two PEO-b-PCL block copolymers were prepared (denoted OCL1 and OCL3), with 0.42 mole fraction of the EO blocks (fEO) for both OCL1 and OCL3, and Mn equal to 4,600 and 11,000 g mol1 for OCL1 and OCL3, respectively. Worm micelles of the OCLs were formed using a cosolvent evaporation method. Taxol (TAX), a hydrophobic drug, and PKH 26, a dye, were confined in the resulting WLMs, and a direct fluorescence visualization contrast was achieved in Figure 9B,

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which showed that worm micelles convert into spheres over a longer time scale. Statistical data of the mean contour length of the OCL led to the same conclusion. Zhang et al. [119] prepared porphyrin-containing microspheres from poly(allylamine hydrochloride)-g-porphyrin (PAH-g-Por MPs) (Figure 9A) via a Schiff base reaction between 2-formyl-5,10,15,20-tetraphenylporphyrin (Por-CHO) and PAH doped in CaCO3 microparticles, followed by template removal. As HCl was introduced to change the pH of the solution to 1, 2, 3, or 4, the polymer exhibited multistate pHresponsive shape evolution after being incubated for different times. Once the CaCO3 template was removed using ethylenediaminetetraacetic acid, PAH-g-Por MPs were obtained because of the aggregation of hydrophobic Por and rearrangement of the hydrophilic PAH chains. At pH 13, the MPs decomposed and self-assembled, growing into nanotubes with different lengths. At pH 4, the MPs expanded and further budded into wormlike self-assemblies, which appeared as smooth and flexible aggregates encompassing denser dispersed structures. The pH-responsive shape evolution was proposed to result from the decomposition of the Schiff base and the protonation of PAH (Figure 9C). At pH 13, the PAH-g-Por MPs were partially hydrolyzed to release different amounts of the Por molecules, which favored noncovalent interactions, such as ππ stacking and hydrophobic interactions, owing to a planar aromatic chemical structure. The released Por molecules served as growth points for the subsequently formed nanotubes in a relatively acidic environment. Nevertheless, the MPs underwent a purely physical transformation below pH 4, as the conditions were not sufficiently acidic to decompose the PAH-g-Por MPs. Stable PWLMs were formed because of the increased protonation of PAH and C=N and the local self-assembly of the PAH-g-Por components.

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Figure 10. (A) TEM images of PGMA-PHPMA micelles before and after morphological transitions

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under various pH conditions. (B) Corresponding schematic illustration depicting the

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dynamic covalent chemistry between CPBA and PGMA that drives such morphological transitions within vesicles, worms, and spheres. [121], Copyright 2017. Reproduced with

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Dynamic covalent compounds encompass a substantial subset of reversible stimuliresponsive polymers, and some of these molecules exhibit pH-induced reversibility elicited via analyte recognition, whereby pH governs the selective binding of unbound molecules with the main body of the polymer chain, involving a subtle change in the fractional packing parameter and a desired morphological change [120]. Deng and coworkers [121] exploited dynamic covalent chemistry to trigger the reversible morphological transitions of PGMA-PHPMA (Figure 3A) vesicles (1/2 ≤ p < 1) by introducing carboxyphenylboronic acid (CPBA), which acts as a specific binding reagent for some of the pendant 1,2-diol groups on the PGMA chains under mildly alkaline conditions (pH~10). As depicted in Figure 10B, PWLMs result from the formation of phenylboronate ester bonds by reducing the fractional packing parameter on two levels: (i) the overall mass of the stabilizer chains increases, and (ii) the formation of each phenylboronate ester expands the stabilizer chain by introducing two anionic charges. Besides, fully reversible worm-to-sphere transitions were also observed for the assembling counterpart when 1/3 < p ≤ 1/2, where the composite dynamic SPWLMs reformed into free-flowing spheres when the pH was returned to the acidic range (pH~5.9) over a wide range of copolymer concentration, and as expected, reversible in situ (de)gelation at higher concentrations was observed. The above results demonstrate the ability to design new pH-responsive polymer worms. Introducing pH-sensitive groups into micelles endows both polyacids and

polybases with the ability to be triggered in different pH regimes. Moreover, the scope of the dynamic covalent chemistry strategy has extended to the pH-dependent hydrolysis of polyelectrolytes. In addition, degradable polymers that display specific responsiveness to subtle acidic and basic changes represent an original approach to develop new pH-sensitive soluble materials. 4. CO2-responsive PWLMs

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CO2 has been broadly investigated as a potential novel trigger for polymers, hydrogels,

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Figure 11. (A) Block copolymers with CO2 responsiveness: O113F11E112, OmSnEp, PEO113-b-P(4VP90-

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r-DEAEMA30), and PS60-b-P(4VP50-r-DEAEMA25). (B) Schematic representation of solvent-driven formation of OmSnEp PWLMs and their morphological alteration after exposure to CO2, in which the black wire, red bar, and blue fiber represent the “O”, “F” and “E” blocks, respectively. (C) TEM images of assemblies from the segmented polymer,

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PEO113-b-P(4VP90-r-DEAEMA30). (a) Micelles treated with CO2 at pH 5.43, (b) micelles treated with HCl at pH 3.32, (c) necklace-like micelles upon CO2 removal using N2 (pH 7.35), and (d) giant worms before CO2 treatment (pH=7.50). [130], [137], Copyright 2015, 2015, respectively. Reproduced with permission from the American Chemical Society and the Royal Society of Chemistry, respectively.

In general, the currently reported CO2 sensitivity is based on a reversible protonation activated by the acidification of the solvent environment. Considering the formation

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of carbonic acid, the combination of CO2 and water is not solid enough to enable reversal of the weak acidization by removing CO2, leading to a controllable pH variation. Consequently, CO2-sensitive moieties such as amine- or amidine-generating hydrophilic compounds, which exhibit high nucleophilicity or basicity and convert into ammonium- or amidinium- bicarbonates, show repeated and reversible responses via alternatingly purging CO2 and inert gases [128132]. Nevertheless, limited studies on PWLMs have utilized the design of CO2 responsiveness (Figure 11A), among which, poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA), a branched tertiary amine-incorporated polymer with pKaH of approximately 6.07.0 [129,131], has been proven as an ideal CO2-switchable material [129131,133137].

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Recently, our laboratory [129] developed a CO2-responsive linear ABC triblock copolymer, which underwent a high level of self-assembly into multicompartment

U

micelles (MCMs). The copolymer contains three well-defined segments in a certain

N

sequence, i.e., a hydrophilic block, poly(ethylene oxide) (O); a fluorinated block,

A

poly(2,2,3,4,4,4-hexafluorobutyl methacrylate) (F), which targeted a super strong

M

segregation regime [28]; and a CO2-sensitive block, PDEAEMA (E). In a subsequent

ED

study, the MCM system from the same triblock copolymer O113F110E112 was extended [130] to diverse morphologies, including PWLMs, driven by adjusting the composition

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of the mixture solvent containing water and ethanol. Once the water content was

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increased to 4050%, the interfacial energy between the “F” block and the polar solvent system drove the formation from spheres to short rods, then to long cylinders and finally to PWLMs. The PWLM system exhibited morphological variation with the stimulus of

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CO2, as bubbling CO2 into the mixture solvent led to the protonation of the “E” block and transformed it from hydrophobic to hydrophilic, inducing an electrostatic repulsion between the CO2-responsive “E” blocks. With an increase in micellar curvature, part of the PWLMs converted back to spherical micelles, as depicted in Figure 11B. In

addition, it is notable that the control of morphological evolution by the solvent-mixing method has been similarly studied at length in the context of self-assembly of multiblock copolymers with divergent affinities in mixed solvents [138], and will be overviewed in Section 6.

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Regarded as a pivotal endogenous metabolite, CO2 has drawn considerable attention as a biological stimulus that can subtly regulate the shape and structure of polymer

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assemblies based on organelle mimicry [127]. The Zhao team successfully employed

CO2 as a physiological stimulus for delicately modulating well-defined polymer

U

micelles [131]. They designed a triblock copolymer to integrate CO2 responsiveness

N

with the multiform initial packing structures, which comprised an outer hydrophilic

A

poly(ethylene oxide) segment (O), a middle hydrophobic poly(styrene) bridging block

M

(S), and a CO2-responsive interior PDEAEMA part (E) (Figure 11A). When dissolved

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in an aqueous solution, O113S72E61 spontaneously formed PWLMs with highly curly and folded structures. Continuous purging with CO2 caused the worms to gradually

PT

straighten and stretch into rigid nanowires with a notable decrease in crimpness (Figure

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12). Additionally, the curvature variation could be reversed by alternating CO2/N2 bubbling. Particularly, the protonated “E” segments hydrated slowly as they were wrapped in the core-forming “S” block in the presence of CO2, and the restricted

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hydration produced a relatively delicate static charge repulsion between the E+ blocks, resulting in the stretching and unfolding of the PWLMs.

IP T SC R U N A M

Figure 12. TEM images of O113S72E61 micelles at different durations of CO2 stimulation and concomitant stretching evolution: (a) no stimulus, (b) 15 min, and (c) 30 min (scale bars:

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150 nm). (d) Average number statistics of the curly points in per nanofiber. (e) CO2induced stretching evolution of PWLMs. [131], Copyright 2013. Reproduced with

PT

permission from the American Chemical Society.

In addition to well-defined block copolymers, block-random segmented copolymers,

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which consist of at least one random copolymer, have also been innovatively explored [113] to realize CO2 responsiveness. Our team [137] achieved a reversible

A

morphological transition from giant WLMs to polymersomes by introducing a blockrandom segmented amphiphilic copolymer, poly(ethylene oxide)-b-P((4-vinyl pyridine)-r-(2-(diethylamino)ethyl

methacrylate)),

i.e.,

PEO113-b-P(4VP90-r-

DEAEMA30) (Figure 11A), in which the PEO block served as a hydrophobic stabilizer

and the random hydrophilic block responded to the stimulation of CO2. In water, the copolymer self-assembled into vesicles, which then quickly fused into giant worms. In the presence of CO2, the giant worms in solution transformed into polymersomes, which could be reverted back to necklace-like worm micelles after depleting CO2 by

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bubbling N2. The 4VP moieties could not be protonated by CO2 because the pH of the CO2-saturated solution was higher than the pKaH of 4VP. Thus, the hydrophobic-

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hydrophilic transition, proceeded via protonation and deprotonation of the CO2responsive moiety PDEAEMA to drive the serial shape variation. In addition, the

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random copolymerized 4VP introduced substantial steric hindrance that restricted

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DMAEMA from being protonated completely, whereas hydrogen bonds formed

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between the 4VP moieties stabilized the giant worms. Figure 11C evidences the above-

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mentioned variation from TEM images. In a recent work, Yin et al. [139] developed a

ED

co-assembling system that combined CO2-sensitive block-random segmented copolymer,

poly(styrene)-b-P((4-vinyl

pyridine)-r-((2-(diethylamino)ethyl

PT

methacrylate)), i.e., PS60-b-P(4VP50-r-DEAEMA25), with a simple copolymer, PEO-b-

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PAA. The DEAEMA units in the random chain interact with the PAA segment into complex coacervated core micelles through electrostatic interaction [140], inducing a wormlike co-assembling micelle to emerge in the DMF/H2O solvent mixture.

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Elongated PWLMs were likewise formed in this co-assembling system as PAA would interact with P(4VP50-r-DEAEMA25) to generate spheres with solvophobic cores, and further merged together into PWLMs. Upon stimulation with CO2, the DMAEMA units in the aggregating cores were protonated, and the wormlike aggregates were

transformed into spherical micelles. This work demonstrates that the co-assembly path is an alternative way to fabricate morphology-tunable micelle systems, and further research on its switching “on/off” property is expected. CO2-switchable PWLMs are part of a newly developed class of smart micelles

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exploiting benign triggers that have low environmental impact and are easily removed without the formation of any contaminative by-products. Nevertheless, the CO2-

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triggering system still exhibits several drawbacks. First, CO2-targeted moieties are still

somewhat limited, and the majority of them require a demanding synthesis. Expanding

U

the selection would broaden the versatility of CO2-responsive materials [125]. Second,

N

the CO2 capture efficiency of pH-responsive polymers is generally low. Finally, only

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5. Redox-responsive PWLMs

M

is relatively high [126].

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highly concentrated CO2 can trigger a response, as the concentration baseline thus far

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Redox stimuli are a relatively intriguing class of triggers with promising applications in physiological environments, because the disulfide bonds, one of the most typical redox responders, can be cleaved into corresponding thiols in the presence of reducing agents, satisfying appropriate degradability as potential drug carriers in the biological environment. Inspired by these studies on WLMs, PWLMs with thioether blocks have become the next promising research interests that would exhibit novel redox sensitivity. Thioethers are generally stable under aerobic conditions [141], but readily respond to reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and hydroxyl radicals. Poly(propylene sulfide) (PPS) was the first hydrophobic block utilized in oxidation-responsive smart micelles, as it features an appropriate balance between high hydrophobicity in a reduced state and high hydrophilicity when oxidized due to its small aliphatic content [141144]. The oxidative destabilization of the PPS block in micelles exploits the hydrophobichydrophilic transition of the thioethers when the sulfide groups are oxidized into hydrophilic sulfoxide and sulfone moieties, which causes a disruption of the micelle stability and enlargement of the curvature of the

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hydrophobic-hydrophilic interface, ultimately triggering morphological transformations. Napoli et al. [145] synthesized an ABA-type triblock copolymer with a morphology that could be irreversibly controlled by oxidation with H2O2. The triblock copolymer comprised two PEG blocks on both ends and a PPS block in between. This triblock copolymer formed vesicles initially at room temperature due to the low Tg of the coreforming PPS (≈230 K) [142,146]. As shown schematically in Figure 13A, the PPS segment is sensitive to oxidizers and can be converted from hydrophobic to hydrophilic upon oxidation by H2O2. The original vesicles could consequently be converted into WLMs in the presence of H2O2.

Figure 13. (A) Schematic image of oxidation-responsive PEG-PPS-PEG vesicles. (B) TEM images of

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vesicles in the presence of different concentrations of H 2O2: (left) 10 vol% and (right) 3 vol%. [194], Copyright 2009. Reproduced with permission from John Wiley & Sons Inc; [146], Copyright 2004. Adapted with permission from the Nature Publishing Group.

At higher concentrations of H2O2, only PWLMs were observed (left, Figure 13B), whereas at lower concentrations of H2O2, both worm micelles and vesicles were observed (right, Figure 13B) because higher concentrations of H2O2 may accelerate the transition of the PPS block from extremely hydrophobic to less hydrophobic.

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However, the transformation of vesicles to PWLMs is not reversible in this case. It may be inferred that the addition of a reducing agent could enable the reversible transition from worm micelles to vesicles. Nonetheless, this new class of oxidationresponsive polymer vesicles may find applications as nanocontainers in drug delivery, biosensing, and biodetection [146]. The introduction of disulfide bonds into the polymer backbone would endow the polymer assemblies with reduction sensitiveness. The Armes group [147] statistically copolymerized a disulfide-based cyclic monomer, 3-methylidene-1, 9-dioxa-5, 12, 13trithiacyclopentadecane-2,8-dione (MTC, Figure 14A), with HPMA, a core-forming block. The desired PWLMs were further obtained for pGMA56-p(HPMA170-statMTC0.85). Addition of a typical reductive agent, tris(2-carboxyethyl) phosphine (TCEP, Figure 14B), introduced a worm-to-sphere transition at pH 8–9 and 20 °C, as shown in Figure 14B. This transition was induced by reduction-degradation at MTC moieties, where cleavage of the disulfide bonds with excess TCEP resulted in irreversible core shrinkage for the micelles. Besides, two cases of reductionswitchable WLMs were also reported by the Abe [148] and Feng groups [149].

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Figure 14. (A) Synthesis of pGMA56-p(HPMA170-stat-MTC0.85) diblock copolymer. (B) TEM images of pGMA56-p(HPMA170-stat-MTC0.85) before and after treating TCEP at pH 8–9. The schematic image shows the variation in packing parameter. [147], Copyright 2016. Reproduced with permission from the American Chemical Society.

Redox stimuli are a relatively intriguing class of triggers with promising applications in physiological environments. It is necessary to confirm that in drug delivery, an

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irreversible disassembling is the key step during stimuli responsiveness, which has directly reduced the necessity of designing and constructing smart PWLM systems transformed from polymer vesicles. Compared to the micelle morphology, scientists would regard the controlled drug release as more important, which might explain the reason for the absence of any other reduction-sensitive PWLMs to date apart from the oxidation responsiveness mentioned above. Apart from micelles, redox-responsive polymers have also been expanded to the field of supramolecular packing, where Yuan et al. [150] opened a new avenue for redox-tunable degradable materials through the electric-charge-dependent host-guest connection, realizing a controllable one-dimensional nanopacking. Therefore, the development of redox-responsive materials has extended beyond site-specific targeting of therapeutic delivery, and hold great promise in smart material fields. 6. Solvent-responsive PWLMs

U

As aforementioned, the self-assembly of amphiphilic block copolymers in solutions

N

can result in the formation of diverse morphologies, determined by both the intrinsic

A

architecture and extrinsic environment [151,152]. Particularly, based on the work of

M

Eisenberg [153], the morphology of a micelle depends on three factors: (i) the stretching

ED

of core-forming chains, (ii) the core-corona interfacial energy, and (iii) the repulsion between coronal chains. In addition to the common stimuli mentioned above, solvent

PT

has been proven to play an essential role in the self-assembly of structures. Both

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changing of solvents [154] and the use of binary solvents [155] have been demonstrated to be efficient in reconstructing micelles, including PB-PEO in a DMF/water mixture [156], PS-PAA in a dioxane/water mixture [157], and PS-PEO in a DMF/acetonitrile

A

mixture [158]. Concerning PWLMs triggered by solvent, multiblock-polymers comprising blocks with divergent affinities toward different solvent systems are constructed to facilitate the prompt response of the copolymers once the solution environment is changed.

Groschel et al. [159] prepared hierarchically self-assembled ABC triblock terpolymers

with

common

blocks,

polystyrene-b-polybutadiene-b-poly(methyl

methacrylate)s (PS-b-PB-b-PMMA, SBM for short, Figure 15A). In contrast to the conventional one-step method for obtaining assemblies, during which copolymers were

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directly dispersed and assembled in solvents, the authors employed a two-step method to achieve very homogeneous distributions of the MCMs. Because of this novel strategy

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and the use of an OsO4 staining method, an abundance of rarely reported spherical micelles and PWLMs with morphologies that could be reversibly changed by altering

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PT

ED

M

A

N

U

the solvent composition were obtained.

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Figure 15. (A) Mechanism for the preparation and directed hierarchical self-assembly of well-defined MCMs. (B, left) Unstained TEM images of the triblock copolymer PS-b-PTFMS-[Ru]PEG in different solvents and (B, right) chemical structure of PS-b-PTFMS-[Ru]-PEG. (C). Schematic representation of the soluble blocks of the triblock copolymer PS-bPTFMS-[Ru]-PEG in different solvents. [159], [160], Copyright 2012, 2009, respectively. Reproduced with permission from the Nature Publishing Group and the Royal Society of Chemistry.

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First, SBM was dissolved in N,N-dimethylacetamide (DMAc), which is a non-solvent for PB, a near-θ solvent for PS, and a good solvent for PMMA, and spherical micelles with a PB core and PS/PMMA mixed corona were formed. Then, the micellar solution was dialyzed against an acetone/isopropanol mixture to trigger the collapse of the PS blocks, as acetone is a poor solvent for PB, a near-θ solvent for PS, and a good solvent for PMMA, whereas isopropanol is a near-θ solvent for PMMA and a non-solvent for both PS and PB. Consequently, MCMs were formed through higherlevel assembly of the polymer. Different polymer compositions led to different final micelle morphologies during the repeated refinement of the A/C (S/M) corona structure of the intermediate subunits: SB2 “hamburgers” of SBM6, SB3 “clovers” of SBM3, SB4 “Maltese crosses” of SBM4, SB7 “footballs” of SBM5, and SBX “footballs” of SBM1 and SBM2 (Figure 15A). More interestingly, the spherical micelles formed from SBM9 could grow into linear WLMs by the assembly of spherical micelles upon addition of a non-solvent of the corona (PS and PMMA) and reverted to spheres upon dialyzing with good solvents for the corona. Consequently, the formation and disintegration of WLMs can be readily controlled by changing the solvent composition, and this strategy can be effectively adopted to design complicated hierarchical structures. Ott et al. [160] synthesized a triblock polymer with hydrophilic, fluorophilic, and hydrophobic segments, PS-b-PTFMS-[Ru]-PEG (PTFMS: poly(paratrifluoromethylstyrene)), by nitroxide-mediated polymerization and supramolecular chemistry. The micellar shape can be tuned via the targeted design and synthesis of amphiphilic macromolecules. In this case, alcohols with different polarities were employed to induce the self-assembly of the terpolymer. The PEG block well dissolved in all types of alcohols tested in the experiment at room temperature, whereas the PS block could not be solvated even at very high temperatures. The PTFMS block, on the other hand, dissolved well in methanol and ethanol, but showed an upper critical solution temperature (UCST) in 1-propanol, 2-propanol, and 1butanol. As presented in Figure 15B, the solvent-affinity reversal caused a solvophobic/solvophilic migration. Different solvophilic/solvophobic ratios in different solvents lead to aggregates with various morphologies (Figure 15C). As mentioned in Section 4, Liu et al. [130] synthesized a CO2-sensitive fluorinated triblock copolymer, O113F110E112, which underwent a solvent-driven formation of PWLMs at 1.0 g L1 in the controlled mixed solvent of ethanol and water. Water was a selective solvent for the “F” and “E” blocks, and with increasing volume of water, the macromolecular assemblies transformed from spheres in pure ethanol to elongated worms at a 40% water ratio and eventually to vesicle-like structures at 50% water before precipitating. The gradient variation in solvent composition and subsequent alteration of solvent affinity resulted in a morphological evolution. Ethanol can also be utilized as a cosolvent to facilitate the morphological transition. Blanazs and

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coworkers [46] copolymerized GMA with water-miscible HPMA by PISA synthesis under aqueous dispersion polymerization conditions and studied the self-assembly behavior of the resulting polymer in water. The growing PHPMA block becomes increasingly hydrophobic and hence drives the in situ self-assembly. The G78-H500 diblock copolymer aggregated into spheres in the absence of ethanol and then became a mixed phase comprising spheres and vesicles in a 10% ethanol mixture. Vesicles are predominantly obtained in 15% ethanol, and both worms and vesicles are observed in 20% ethanol. This morphological evolution was ascribed to the swelling effect of the ethanol cosolvent on the PHPMA cores, which substantially destabilized the aggregation efficiency and reduced the interfacial tension between the two blocks. The solvent-driven strategy has inspired a nascent effort to fabricate PWLMs from well-defined copolymers, the stimuli-responsiveness of which is concurrently established and regulated by constructing relevant functionalized blocks. In fact, the window for the pure worm phase is relatively narrow and is surrounded by mixed-phase regions of spheres and vesicles. Well-defined spheres and vesicles can be easily obtained experimentally, whereas obtaining worms is more challenging. Despite being an inefficient trigger in terms of smart responsiveness, solvent induction is an intuitive way to continuously manipulate the morphology of amphiphilic multiblock copolymers in solutions and is broadly utilized in the search of appropriate phase windows for PWLMs and in the establishment of new phase diagrams [46]. 7. Dual stimuli-responsive PWLMs

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Academic studies normally focus on broadening and optimizing the smartness of micelle systems in different categories, as presented in the previous sections, whereas Mother Nature, which represents an outstanding inspiration for stimuli-responsive polymer materials, shows countless natural responses triggered by a combination of dual or multiple stimuli. For example, various biological processes based on macromolecules such as proteins, polysaccharides, and nucleic acids are known to often be a result of adaptation to multiple environmental changes rather than a single one [161]. Systems that are responsive to two stimuli provide an even greater level of control and are of immense importance for biologically relevant applications [162]. From the perspective of biomimicry, the exploration of multi-responsive polymer materials is driven by an urge to mimic the complexity of living systems [163,164]. 7.1 Dual stimuli-responsive PLWMs with designed end-groups Of particular relevance to what has been introduced in the preceding sections, PISA has become a widely recognized and a highly versatile route to diblock copolymer self-assemblies [8,9,11,20]. Armes and co-workers [45] efficiently synthesized PGMA-PHPMA nonionic worm gels that exhibited thermo- and pH-responsive

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behaviors using a carboxylic acid-functionalized RAFT agent. The former transition is the result of the surface plasticization of the PHPMA core-forming block, whereas the latter transition is caused by the ionization of a single terminal carboxylic acid group located at the end of the PGMA stabilizer block [105]. Inspired by the concept of combination, Lovett et al. [165] demonstrated the complex stimuli-responsiveness of PGMA-PHPMA vesicles in aqueous solutions via end-group design. Carboxylated HOOC-PGMA43 (Figure 3A) was utilized as a macro-CTA to initiate the RAFT aqueous dispersion polymerization of HPMA. When the DP of the HPMA block was 175, 200, 225, or 250, the resulting copolymer further assembled into vesicles in the solution. When the pH of the vesicular solution was increased from 3.5 to 6.0, the initially turbid fluids containing HOOC-PGMA43-PHPMA175 and HOOCPGMA43-PHPMA200 gradually transformed into free-standing translucent gels because of the pH-triggered order-order morphological transition induced by the ionization of the terminal carboxyl group, whose pKa is approximately 4.7 [105]. As the pH was increased, the deprotonation of the terminal acid group increased the effective volume fraction of the adjacent core-forming PGMA, thus lowering the packing parameter, p. The resulting new worm gels exhibited a macroscopic architectural transition. Temperature-dependent rheological studies indicated that the pH-responsive copolymer system was sensitive to thermal triggers, as the HOOC-PGMA43PHPMA200 worm gels underwent degelation at a neutral pH upon cooling from 25 °C to approximately 4 °C. The phase transition occurred when the loss modulus (G) exceeded the storage modulus (G), which is generally defined as the CGT. The mechanism of the thermo-sensitivity was consistent with the surface plasticization proposed by Blanazs et al. [45], i.e., PHPMA cores become extensively hydrated upon cooling, ultimately resulting in a sol-gel transition. Importantly, both the pH and thermal switches are irreversible, which is probably due to the kinetic barrier preventing the worms from re-forming into the original vesicles. In addition, adding salts to the initial vesicles would prevent the phase transition under pH stimulation because of the electrostatic screening effect. An additional structural modification enabled the dual-responsive reversibility of the order-order transition of PGMAPHPMA in a semi-dilute solution [166]. In a subsequent complementary study, the same group [167] synthesized morpholineend-capped PGMA43-PHPMAy diblock copolymers, where the y values were 190, 200, 222, and 230. The pKa of the morpholine end-group of a nearly identical MPETTC-PGMA50 macro-CTA was recently approximated as 6.3 [47]. When treated with HCl to lower the pH from neutral to 3.0 for 48 h, the free-flowing turbid fluids containing MPETTC-PGMA43-PHPMA190 and MPETTC-PGMA43-PHPMA200 were observed to transform into free-standing gels, a macroscopic manifestation of the pHinduced morphological transition from vesicles to PWLMs [47]. The mechanism

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herein was in accordance with the PISA of the morpholine-functionalized block, that is, complete protonation of the terminal morpholine group at pH 3.0 leads to a subtle increase in the volume fraction of the hydrophilic PGMA blocks, which in turn lowers the packing parameter, p, from the vesicle regime to the worm regime [6]. The worm gels protonated at pH 3.0 were successively examined by temperature-dependent oscillatory rheology from 20 °C to 4 °C. As expected, a cooling-induced degelation was observed as the CGT of 10 °C was reached because of the worm-to-sphere transition induced by the lowered temperature. Moreover, regelation occurred at 12 °C as the temperature was increased again, confirming the reversibility of this thermoresponsiveness, which was established as a synergistic effect of both pH and temperature. The former stimulus increases the volume fraction of the PGMA blocks due to the protonation of a single morpholine end-group, whereas the latter stimulus simultaneously enhances the degree of hydration of the PHPMA core-forming block and further reduces the packing parameter. Consequently, a vesicle-worm-sphere order-order morphological variation with favorable reversibility was designed. A summary of the end-group-functionalized designed PWLMs and their aforementioned dual responsiveness is provided in Table 1.

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Table 1.

Summary of Data Obtained for HOOC-PGMA43-HPMAX and MPETTC-PGMA43-HPMAy Diblock Copolymer Vesicles Illustrating Their pH- and Thermoresponsive Behaviors. Adapted with permission from [165], Copyright 2016, the American Chemical Society; [167], Copyright 2016, the Royal Society of Chemistry.

HOOC-PGMA43PHPMA200 a

Spheres and spherical dimers

Yes

Yes

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MPETTC-PGMA43PHPMA200 b

Morphology after 20 to 5 °C temperature switch

Dual respons ive?

Reversib le？

Yes

Worms

Yes

No

No

Yes

No

Worms

No

Yes

Yes

Worms

No

Yes

Yes

M

Worms

Results collected from Ref. [164]; b) Results collected from Ref. [166].

A

a)

Yes

Therm orespons ive?

Morphology after pH 7.0 to 3.0 switch

A

Yes

PT

MPETTC-PGMA43PHPMA190 b

Morphology after pH 3.5 to 6.0 switch

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HOOC-PGMA43PHPMA175a

pHresponsive ?

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The Lowe team [168] recently reported triply responsive nanoparticles based on carboxylate group coronal-terminated poly[oligo(ethylene glycol) methyl ether methacrylate-b-3-phenylpropyl methacrylate] (poly(OEGMA27-b-PPMA36)). As shown schematically in Figure 16A, this polymer was able to elicit three different types of responses in aliphatic alcohols when exposed to external stimuli. The copolymer nano-assembly exhibited two distinct and fully reversible thermal responses as well as the end-carboxylate-induced pH sensitivity depicted in Figure 16A: (i) a worm-to-sphere order-order transition triggered by the increased surface plasticization of the pPPMA cores in methanol, (ii) a unique disorder-order transition corresponding to the onset of solvation of the pOEGMA coronas prompted by the UCST behavior of the pOEGMA chains (~30 °C) in ethanol [11], and (iii) a worm-tosphere transition upon adding an organobase in methanol driven by the deprotonation of the acid functionality in the stabilizing end-block. The delicate triply intramolecular responsiveness was verified by temperature-dependent NMR (Figure 16B) with distinct variations in the four characteristic resonances, demonstrating the validity and reversibility of both the inner and outer chains.

Figure 16. (A) Multi-responsive soft matter nanoparticles based on carboxylate corona end-groupfunctionalized p(OEGMA27-b-PPMA36) copolymers eliciting different types of responses.

Four characteristic groups are labeled with four colors for 1H NMR. (B) 1H NMR spectra of p(OEGMA27-b-PPMA36) recorded in ethanol highlighting four key resonances upon heating from 5 °C to 70 °C and cooling from 70 °C to 25 °C. [11], Copyright 2017. Adapted with permission from John Wiley & Sons Inc; [168], Copyright 2016. Reproduced with permission from the Royal Chemical Society.

7.2 PWLMs with specific dual-responsive blocks

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PDMAEMA has been extensively studied for its thermal and pH dual-responsive characteristics [169172]. The LCST of PDMAEMA ranges widely from 30 °C to 50 °C depending on pH, ionic strength, and molecular weight [173]; thus, fundamental thermo-reversible macroscopic degelationgelation was intuitively expected because of its worm-to-sphere transition [172,174,175]. Meanwhile, with its branched terminal tertiary amine group, PDMAEMA is sensitive to pH due to protonation/deprotonation [176178]. Using PDMAEMA as a functional joint, Smith et al. [179] developed a temperature-induced micellar growth system, including the desirable WLMs. They synthesized the diblock copolymer poly(N,Ndimethylaminoethyl methacrylate)x-b-(N-isopropylacrylamide)y, P(DMAEMA165-bNIPAMy), in which y was 102, 202, or 435. RAFT polymerization was utilized to prepare the amphiphilic diblock copolymer, and then Au nanoparticles (AuNPs) were employed to stabilize the subsequently formed micelles by adding NaAuCl4 into the micelle solutions at 50 °C to react with the amines of PDMAEMA. Generally, micelles were formed, as verified by the abrupt increase in particle diameter with increasing temperature. Before being cross-linked by the AuNPs, the influence of polymer composition, copolymer concentration, pH, and salt concentration on the micelles’ critical aggregation temperatures (CAT) was studied. It was found that a higher polymer concentration, higher pH, and higher PNIPAM ratio might promote micelle formation upon heating, which is consistent with the CAT behavior, whereas added salts may lower the CAT value. More specifically, two distinct distributions arose above 46 °C at pH 7, which reflect the coexistence of spherical micelles and WLMs, as confirmed from the TEM images. Both heating and pH regulation would facilitate the reformation of PWLMs. In particular, cross-linking with AuNPs may slightly increase the size of both spherical micelles (61 nm to 78 nm) and WLMs (237 nm to 289 nm). Temperature-induced assembly in aqueous media could provide an important pathway for biologically relevant applications [179]. Importantly, despite being broadly utilized as a component in smart hydrosoluble polymers, PNIPAM has been determined to have appreciable toxicity and experiences problematic interactions with proteins, which would certainly impede its biocompatibility [180182]. 8. Rheological features and applications of PWLMs

Importantly, PWLM solutions are rheologically detached and thus display much weakened viscoelasticity compared with small molecular surfactant-based WLMs, which may change the basic thought process regarding PWLMs. The interest in smart surfactant WLMs lies in their microscale dimensional responsiveness, which leads to

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macroscopic manifestations of the ceaseless dynamic reconstruction and engenders remarkable rheological characteristics [183]. In contrast, their mega-analogue,

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PWLMs, are viscoelastically inferior in comparison some properties. Particularly, the

Maxwellian behavior of typical surfactant WLMs is explained kinetically by local stress

U

relaxing through a combination of reptation (curvilinear diffusion behavior, defined by

N

τrep) and breakage/recombination (submicellar kinetics, defined by τb) mechanisms.

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Elongated worms are characteristically slow diffusing and fast breaking [183], causing

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a prominent decrease in ζ (=τb/τrep), as conventionally demonstrated in surfactant

ED

WLMs [184]. In the case of PWLMs, the viscoelastic spectra deviates from a Maxwellian simulation at low and intermediate frequencies, revealing a consecutive

PT

spectrum of relaxation time (τR) and an increase in ζ [185187]. This irrational

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attenuation has been ascribed to an impediment of micellar rearrangement [185]. When dispersed in a polar solvent, extended polymer surfactants (see, amphiphilic block copolymers) exert much stronger aggregating potential due to the extended non-

A

polarity, resulting in a relatively low critical micelle concentration (CMC) in case of a small surfactant [188]. Consequently, the stiff interchain packing strikingly solidifies the PWLM cores, where chain relaxation is ultimately prolonged. Despite not being completely frozen, the PWLM cores impede chain relaxation, which prevents micelles

from breaking and potentially re-forming as Maxwellian fluids [185]. Evidence for the aforementioned slow kinetics was directly obtained by cryogenic transmission electron microscopy (cryo-TEM), which showed perceptible exchange within the PWLMs and intermolecular equilibrium was never achieved [189]. Furthermore, PWLM-based

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Pluronic triblock copolymers have been reported to depart from and draw near conformity with the Maxwell law before [186] and after [190] mixing ethanol into a

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polar solvent, respectively, demonstrating the close ties between core solvation and chain relaxation.

U

In addition to the mechanical deviation from the rheological perspective, an

N

assembling discrepancy mechanism was newly proposed, declaring the “multiple

A

contacts” model to accounts for the 3D network within free-standing PWLMs gels,

M

rather than the widely accepted “worm entanglement” model followed from surfactant

ED

worms. The Armes group [191] adopted percolation theory to model the relative flexible PWLMs to calculate the practical percolation threshold, Фc, by utilizing the

PT

SAXS-determined weight-average worm contour length, Lw, and the mean worm cross-

CC E

sectional radius, Rw. Herein the percolation theory was simplified to mathematically fit the high anisotropy of the PWLMs. The percolation theory predicted Фc was in fair agreement with the experimental Фc estimated by tube inversion tests, verifying the

A

validity for the hypothesis that the continuous 3D network of PWLMs forms primarily via multiple contacts between adjacent worms, rather than as a result of worm entanglements. Comprising both the flexible PWLM model and the stiff one, this theoretical derivation was of high reliability in regard to the micelle dynamic behavior

for the stimuli-responsive worms and the design of next generation diblock copolymer worm gels. In the field of stimuli-responsive materials, potential applications have been extensively pursued over the past decade. Smart PWLMs in particular have drawn

IP T

interest for a wide range of applications. Considering their enhanced stiffness compared to lipid-based micelles, SPWLMs possess optimal micellization stability for delivery

SC R

via the shape distortion of hierarchical organizations in response to a range of

environmental triggers [14,192]. Particularly, thermo-switchable worm gels and

U

thermo-induced gel-to-fluid transitions provide a strategy for designing a synthetic

N

alternative for the solvent-free cryopreservation of red blood cells. In combination with

A

poly(vinyl alcohol), a common ice-recrystallization inhibitor, the copolymer worms

M

retained their ability to form free-standing gels upon warming to room temperature after

ED

initial thawing, suggesting an attractive in situ gelatinizing mixture for future whole blood cryopreservation and tissue-engineering applications [193]. Well-defined worm-gel

assemblies

PT

synthetic

with

precisely

controlled

thermosensitive

CC E

conformations are promising due to the introduction of coil-helical-labeled polypeptides [30], which further permits the biocompatible micellization regulation

A

and improves the smart assembly behavior in vivo. Structurally distinctive, elongated PWLMs exhibited drug encapsulation of TAX,

which improved by approximately two times compared to drug encapsulation by spherical micelles of the same diameter [33,194]. Combining mechanical stability with morphological flexibility has led to SPWLMs with accurately controlled order-order

transitions and thus provided the morphological foundation for environmentally adaptive drug loading/release. The drug-releasing capability of OCL PWLMs was established in the preceding section [50], demonstrating the competitiveness of biocompatible worms in terms of loading targeted drugs. In response to pH variations,

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SPWLMs degrade into spheres and consequently accomplish drug release [13]. Moreover, owing to the possibility that multilevel-triggered PWLMs are more

SC R

biomedically adaptable owing to the intricacy of the physiological environment [11],

the field of PWLM carriers and their reversible polymorphism will continue to grow

U

rapidly. Conversely, PWLM gels are typically formed in a narrow compositional

N

window [6]; thus, subtle variations in the packing parameter lead to amplified disparity.

A

In other words, PWLMs are extremely sensitive and high powered in their response

M

behavior. In summary, the versatility of SPWLMs in responding to multiple triggers

ED

through creative mechanisms has been validated, thus authenticating their importance for the realization of smart materials.

PT

9. Conclusions and perspectives

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Substantial progress has been achieved during the last decade in designing stimuliresponsive PWLMs due to their versatility and simple design principles. Owing to the introduction of stimuli-sensitive units, the structurally distinctive amphiphilic

A

copolymers reconstruct their assembly pattern in response to changes in the packing parameters induced by external triggers, including temperature, pH, CO2, solvent, and redox, together facilitating a morphological transition of WLMs into spheres, vesicles, and assorted MCMs. Reorganization of the aggregate geometry induces a concomitant

modification of the fluid properties when switched “on” and “off”, and reversible phase transitions are broadly observed macroscopically, some of which even signify functional “gel-sol” transformations as entangled PWLMs reorganize into isotropic micelles. Many PWLMs depart from the behavior of a typical Maxwellian fluid, as

IP T

copolymer surfactants are so densely packed in the core of the worm that chain relaxation is retarded at low and intermediate frequencies, leading to stabilized

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wormlike aggregation. All these marvelous responsive behaviors indicate the

prospective uses of PWLMs in biomedical applications, drug delivery, nanostructured

U

materials, and sensors.

N

In the future, progress toward the utilization of untested triggers such as illumination,

A

ultrasonic sound, microwaves, and magnetic fields will be made. Multi-stimuli-

M

responsive PWLMs with better biocompatibility should be an area of focus to fabricate

ED

drug carriers with high capacity, accurate release ability, and tunable response to body temperature by changing the attached moieties. The development of PWLMs

PT

comprising dendritic block copolyampholytes is in the early stages, and more

CC E

sophisticated assembly systems with special architectures continue to be of great interest. Meanwhile, the theoretical basis of copolymer packing commonly invokes the packing parameter concept, which is, however, merely an empirical concept for

A

interpreting specific packing behavior rather than a predictable theory for calculating the micelle morphology a priori for a given set of conditions. In future, priority should be given to the application of computational chemistry in this attractive but complex field, to facilitate direct access to more types of structures and to obviate the necessity

of formulating full phase diagrams experimentally. Moreover, hybridizations between PWLMs with nanomaterials, biosensors, and other functional materials should be further considered, as these developments would provide a new outlook on distinguished stimuli-responsive materials. Overall, nanoscale morphological

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variations offer an emergent and rich toolbox for building dynamical macroscopic behaviors, and further progress would provide guidance to future formulation

SC R

rationales.

U

Acknowledgements:

N

The authors are grateful for financial support from the opening fund from the State Key

A

Laboratory of Polymer Materials Engineering (sklpme2014-2-06) and National Natural

ED

M

Science Foundation of China (Grant Number 21273223).

[1]

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